Method of producing iodizing agent, and method of producing aromatic iodine compound

ABSTRACT

A method of the present invention, for producing an iodizing agent, includes the step of electrolyzing iodine molecules in a solution by using an acid as a supporting electrolyte. This realizes (i) a method of producing an iodine cation suitable for use as an iodizing agent that does not require a sophisticated separation operation after iodizing reaction is completed, and (ii) an electrolyte used in the method. Further, a method of the present invention, for producing an aromatic iodine compound, includes the step of causing an iodizing agent, and an aromatic compound whose nucleus has one or more substituent groups and two or more hydrogen atoms, to react with each other under the presence of a certain ether compound. This realizes such a method of producing an aromatic iodine compound that position selectivity in iodizing reaction of an aromatic compound is improved.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a divisional of U.S. patent application Ser. No.12/530,274 filed on Sep. 8, 2009, which is a 371 of PCT/JP2008/054184filed on Mar. 7, 2008 and claims priority to Japanese Application No.2007-061067 filed on Mar. 9, 2007 and Japanese Application No.2007-061068 filed on Mar. 9, 2007, which are hereby incorporated hereinby reference in their entirety.

TECHNICAL FIELD

The present invention relates to: a method of producing an iodizingagent; and an electrolyte used in the method. The present inventionparticularly relates to: a method of producing an iodizing agent byobtaining an iodine cation by electrolyzing iodine molecules; and anelectrolyte used in the method. Further, the present invention relatesto a method of producing an aromatic iodine compound, particularly, amethod of producing an aromatic iodine compound, which is improved inselectivity of a binding position of iodine.

BACKGROUND ART

There has been demand in a wide variety of fields for an aromatic iodinecompound in which an iodine atom is bound to a nucleus of an aromaticcompound, as an intermediate used for various organic synthesis. Inorder to produce such an aromatic iodine compound, a method of using aniodine cation has been known. In the method, the iodine cation generatedby electrolysis is used as an iodizing agent (see Patent Literature 1and Non Patent Literatures 1 through 3). The iodine cation is asignificantly-effective iodizing agent having high reactivity. Forexample, Non Patent Literatures 1 and 2 disclose a method of producingan iodine cation by electrolyzing iodine molecules by using metal saltas a supporting electrolyte in an organic solvent (acetonitrile).Further, Non Patent Literatures 1 and 2 disclose that the iodine cationthus obtained was caused to react with various aromatic compounds.Furthermore, Non Patent Literature 3 discloses a method of producing aniodine cation by using quaternary ammonium salt as a supportingelectrolyte.

Meanwhile, in such iodizing reaction, a binding position of an iodineatom is determined in accordance with a sort of a substituent groupbound to an aromatic compound. That is, the iodine atom is metaoriented, or ortho-para oriented. Here, “meta oriented” means a propertythat the iodine atom is bound to an aromatic compound in a meta-positionwith respect to a substituent group, and “ortho-para oriented” means aproperty that the iodine atom is bound to an aromatic compound in eitheran ortho-position or a para-position, with respect to a substituentgroup. In a case where the iodine atom is ortho-para oriented, a productin which iodine is bound in the ortho-position, and another product inwhich iodine is bound in the para-position, are mixed together in aresultant product of the reaction.

In the iodizing reaction in which iodine is ortho-para oriented asdescribed above, in some cases, the product in which iodine is bound inthe ortho-position, and the product in which the iodine is bound in thepara-position are obtained at a ratio of substantially 1:1.

However, in recent years, there has been demand for an improvement inselectivity (hereinafter, referred to as “position selectivity” in somecases) of a binding position of an iodine atom in such iodizingreaction. Patent Literature 1 and Non Patent Literature 4 disclose aproduction method whose purpose is an improvement in selectivity of thebinding position of iodine. Specifically, Patent Literature 1 describesthat if iodine molecules are subjected to electrolytic oxidation withthe use of a carbon electrode, and then toluene is iodized, a compoundin which iodine is bound in the para-position can be obtained more inamount than a compound in which iodine is bound in the ortho-position.Further, Non Patent Literature 4 describes that toluene was iodized in asolution containing methyl ester orthoformate having three ester bonds,so that the product in which iodine is bound in the ortho-position, andthe product in which iodine is bound in the para-position, were obtainedat a ratio of 3:7.

CITATION LIST

Patent Literature 1

Specification of EP Patent No. 0376858 B (Publication Date: Jul. 4,1990)

Non Patent Literature 1

L. L. Miller, E. P. Kujawa, C. B. Cambell, “Iodation withelectrolytically generated iodine (I)” J. Am. Chem. Soc., 92, 2821,(1970)

Non Patent Literature 2

L. L. Miller, B. F. Watkins, “Scope and mechanism of aromatic iodinationwith electrolytically generated iodine (I)” J. Am. Chem. Soc., 98, 1515,(1976)

Non Patent Literature 3

R. Lines, V. D. Parker, “Electrophilic aromatic substitution by positiveiodine species. Iodation of deactivated aromatic compounds” Acta Chem.Scand., B34, p 47, (1980)

Non Patent Literature 4

T. Shono, Y. Matsumura, S. Katoh, K. Ikeda, T. Kamada, “Aromaticiodination by positive iodine active species generated by anodicoxidation in orthoformate” Tetrahedron Letters, 30, 1649, (1989)

SUMMARY OF INVENTION

In order to obtain a target iodine compound, it is necessary to separatea supporting electrolyte from a resultant product after the iodizingreaction is completed. In a case where salt is used as the supportingelectrolyte (as in Non Patent Literatures 1 through 3), columnchromatography is required depending on a sort of salt. It is difficultto apply a separation operation employing the column chromatography toindustrial production. This has been one of obstacles toindustrialization of the method of producing an aromatic compound byusing an iodine cation generated by electrolysis. For this reason, therehas been demand for development of a method of producing an iodizingagent, which method (i) does not require a sophisticated separationoperation for isolation of a target iodine compound after the iodizingreaction is completed, and (ii) realizes industrial production of thetarget iodine compound.

Further, the inventors of the present invention confirmed that with anyone of the methods disclosed in Patent Literature 1 and Non PatentLiterature 4, it is not possible to improve a generation rate of anaromatic iodine compound in which iodine is bound to an aromaticcompound in the para-position. Therefore, there has been demand fordevelopment of a method of producing an aromatic iodine compound, whichmethod realizes iodizing reaction in which position selectivity isimproved.

The present invention is made in view of the problems. An object of thepresent invention is to realize: a method of producing an iodizingagent, in which method (a) an iodine cation is obtained by electrolysis,and (b) in a case where the iodine cation thus obtained is used as aniodizing agent, it becomes unnecessary to carry out a sophisticatedseparation operation after iodizing reaction is completed; anelectrolyte used in the method; and a method of producing an aromaticiodine compound, in which method position selectivity of iodine isimproved.

A method of the present invention, for producing an iodizing agent,includes the step of electrolyzing iodine molecules by using an acid asa supporting electrolyte.

In the method of the present invention, for producing an iodizing agent,the acid is preferably at least one selected from the group consistingof: sulphonic acids and phosphoric acids, the sulphonic acids beingrepresented by the following General Formula (1):

R¹SO₃H   (1)

(where: R¹ is one selected from the group consisting of a hydroxylgroup, a C₁₋₆ alkyl group, a phenyl group, and a naphthyl group; in thealkyl group, a hydrogen atom may be substituted with a fluorine atom;the phenyl group and the naphthyl group may have a substituent group),and the phosphoric acids being represented by the following GeneralFormula (2):

(where: R² and R³ are, identically or differently, a hydrogen atom, aC₁₋₁₀ alkyl group, or a phenyl group; and the phenyl group may have asubstituent group). It should be noted that, in the present invention,examples of the phosphoric acids include ester phosphate.

In the method of the present invention, for producing an iodizing agent,the solution preferably contains an organic solvent.

In the method of the present invention, for producing an iodizing agent,the organic solvent is preferably at least one selected from the groupconsisting of aliphatic nitrile, alcohol, a chlorinated solvent,aliphatic amide, cyclic ether, and nitromethane.

The method of the present invention, for producing an iodizing agent,employs an acid as a supporting electrolyte. Therefore, in a case wherean iodine cation is used as an iodizing agent to synthesize an iodinecompound, it is possible to easily separate the supporting electrolyteafter reaction is completed. The inventors of the present inventionfound, as a result of diligent study, that in place of salt, an acid canbe used as a supporting electrolyte in electrolysis of the iodinemolecules. An acid can be removed by, for example, neutralizationreaction, without separation process by column chromatography. In otherwords, with the present invention, it is possible to obtain an iodinecation that does not require a sophisticated separation operation afterthe iodizing reaction is completed. The iodine cation obtained by themethod of the present invention is suitable for use as an iodizing agentfor various compounds.

Non Patent Literature 3 discloses a method in which iodine molecules areelectrolyzed in an organic solvent to which trifluoroacetic acid isadded, so as to obtain an iodine cation that can be used for iodizingvarious aromatic compounds. However, with the method disclosed in NonPatent Literature 3, trifluoroacetic acid does not function as asupporting electrolyte.

An electrolyte of the present invention contains an acid used as asupporting electrolyte, and iodine molecules, the acid having aconcentration of not less than 0.01 mol/L but not more than 19.0 mol/L.

In the electrolyte of the present invention, a concentration of theiodine molecules is preferably not less than 0.1 percent by mass but notmore than 50 percent by mass. It should be noted that, in the presentinvention, “electrolyte” is a solution which contributes to theelectrolysis without having any change. Therefore, in a case where asolution out of the range described above is prepared, and from thesolution, a solution within the range described above is obtained by aknown concentration preparing process (dilution or concentration) beforeelectricity is applied, such a solution is also included in a range ofthe electrolyte of the present invention.

The electrolyte of the present invention is preferably used as anelectrolyte for obtaining an iodine cation by electrolyzing iodinemolecules.

By carrying out the electrolysis by use of the electrolyte of the presetinvention, it is possible to obtain the iodine cation which is suitablefor use as an iodizing agent for various compounds.

Further, the inventors of the present invention found, as a result ofdiligent study on production of an aromatic iodine compound in whichposition selectivity of iodine is improved, that by causing an iodinecation and an aromatic compound whose nucleus has one or moresubstituent groups and two or more hydrogen atoms, to react with eachother under the presence of at least one selected from the groupconsisting of a certain acyclic ether compound and a certain cyclicether compound, it is possible to improve the selectivity of a bindingposition of iodine with respect to a substituent group of an aromaticcompound.

A method of the present invention, for producing an aromatic iodinecompound, includes the step of (a) causing an iodizing agent, and anaromatic compound whose nucleus has one or more substituent groups andtwo or more hydrogen atoms, to react with each other under the presenceof at least one selected from the group consisting of cyclic or acyclicether compounds being represented by the following General Formula (3):

(where m is any integer in a range from 2 to 6; n is an integer not lessthan 1; R¹ and R² are, identically or differently, a hydrogen atom or aC₁₋₁₀ alkyl group; R³ and R⁴ are, identically or differently a hydrogenatom or a C₁₋₁₀ alkyl group).

Further, in the present invention, the alkyl group may be substituted,and includes, for example, an alkyl group having a thioether bond.

In the method of the present invention, for producing an aromatic iodinecompound, the cyclic ether compound preferably contains a C₃₋₁₂ ring.

In the method of the present invention, for producing an aromatic iodinecompound, the iodizing compound is preferably an iodine cation.

The method of the present invention, for producing an aromatic iodinecompound, preferably further includes the steps of: separating a solidreaction product from a reaction solution obtained in a reaction stepdescribed above; and recrystallizing the reaction product thus separatedfrom the reaction solution.

The method of the present invention, for producing an aromatic compound,preferably further includes the step of isolating a reaction product bycarrying out distillation process with respect to a reaction solutionobtained in a reaction step described above.

A system of the present invention, for producing an aromatic iodinecompound includes: a first tank for storing an aromatic compound havingone or more substituent groups; a second tank for storing at least oneselected from the group consisting of cyclic or acyclic ether compounds;and a third tank for storing an iodizing agent.

With a method of the present invention, for producing an aromatic iodinecompound, it is possible to improve selectivity of a binding position ofan iodine atom by carrying out iodizing reaction under the presence of acertain acyclic ether compound and a certain cyclic ether compound.Therefore, with the preset invention, it is possible to efficientlyproduce a single product by decreasing a generation rate of an isomer.

Additional objects, features, and strengths of the present inventionwill be made clear by the description below. Further, the advantages ofthe present invention will be evident from the following explanation inreference to the drawings.

DESCRIPTION OF EMBODIMENTS

[1. Method of Producing Iodizing Agent]

The following description explains details of a method of the presentinvention, for producing an iodizing agent. The method of the presentinvention, for producing an iodizing agent, includes the step ofelectrolyzing iodine molecules in a solution containing an acid whichcan function as a supporting electrolyte.

1-1. Electrolyte

An electrolyte of the present invention contains an acid and iodinemolecules.

(Solvent)

A solvent dissolves the iodine molecules and the acid, so as tocontribute to electrolysis of the iodine molecules. Such a solvent ispreferably an organic solvent. The organic solvent may be at least oneselected from the group consisting of aliphatic nitrile, alcohol, achlorinated solvent, aliphatic amide, cyclic ether, and nitromethane.Specifically, examples of the organic solvent include: acetonitrile;propionitrile, butyronitrile; isobutyronitrile; valeronitrile;isovaleronitrile; pivalonitrile; hexanenitrile; methanol; ethanol;propanol; isopropanol; butanol; isobutanol; tert-butanol; chloroform;dichloromethane; carbon tetrachloride; 1,2 -dichloroethane;1,1,1-trichloroethane; 1,1,2-trichloroethane; N,N-dimethylformamide;N,N-dimethylacetamide; N-methylpyrrolidone; N-methylpiperidone;tetrahydrofuran; 1,4-dioxane; tetrahydropyran; and nitromethane.

(Acid)

The method of the present invention, for producing an iodizing agent,employs an acid as a supporting electrolyte. In descriptions of thepresent specification, the “acid” means an acid that becomes dissociatedinto ions in a solvent, and plays a role of leading, into the solvent,electricity which is necessary for the electrolysis.

The acid is preferably at least one selected from the group consistingof: sulphonic acids and phosphoric acids, the sulphonic acids beingrepresented by the following General Formula (1):

R¹SO₃H   (1),

(where: R¹ is one selected from the group consisting of a hydroxylgroup, a C₁₋₆ alkyl group, a phenyl group, and a naphthyl group; in thealkyl group, a hydrogen atom may be substituted by a fluorine atom; andthe phenyl group and the naphthyl group may include a subsutituentgroup), and the phosphoric acids being represented by the followingGeneral Formula (2):

(where: R² and R³ are, identically or differently, a hydrogen, a C₁₋₁₀alkyl group, or a phenyl group; and the phenyl group may have asubstituent group).

Examples of the sulphonic acids include: sulfuric acid; methanesulphonicacid; ethanesulphonic acid; benzenesulphonic acid; p-toluenesulphonicacid; and trifluoromethanesulphonic acid. Examples of the phosphoricacids include: phosphoric acid; methylphosphoric acid; butylphosphoricacid; isodecylphosphoric acid; 2-ethylhexylphosphoric acid; andphenylphosphoric acid.

A concentration of an acid in the electrolyte is not less than 0.01mol/L but not more than 19.0 mol/L, preferably not less than 0.05 mol/Lbut not more than 10.0 mol/L, more preferably, not less than 0.1 mol/Lbut not more than 5.0 mol/L. In a case where the concentration of theacid is less than 0.01 mol/L, the acid cannot cause electricity to flowin the solution, that is, the acid cannot function as the supportingelectrolyte. Further, in a case where the concentration of the acid ismore than 19.0 mol/L, it becomes difficult to prepare the concentrationof the acid.

(Iodine Molecules)

In the method of the present invention, for producing an iodizing agent,iodine molecules are electrolyzed. This eliminates the need to carry outseparation process with respect to a metal ion derived from an iodinemetal compound, after iodizing reaction is completed. Further, in a casewhere the iodine metal compound is used, a monovalent iodine anionexists in the solvent. For this reason, in order to obtain the iodinecation, it is necessary to extract two electrons. On the other hand, ina case where the iodine molecules are used, it is possible to generatethe iodine cation by extracting only one electron. This allows areduction in amount of electricity for the electrolysis. A content ratioof the iodine molecules in the electrolyte is not less than 0.1 percentby mass but not more than 50 percent by mass, preferably not less than0.5 percent by mass but not more than 25 percent by mass, morepreferably 1.0 percent by mass but not more than 10 percent by mass.

1-2. Production of Iodine Cation

The electrolysis is carried out with the use of the electrolytedescribed above, so as to obtain the iodine cation in accordance withthe following Reaction Formula (4).

The electrolysis can be carried out with the use of an electrolyzingdevice in which two rooms are provided for an anode and a cathodeseparately and respectively, for example. In the room for the anode, theiodine molecules, the supporting electrolyte, and the solvent areprovided, and in the room for the cathode, the supporting electrolyteand the solvent are provided. It is preferable that the reaction takesplace while these thus provided are agitated. The reaction can becarried out at a temperature of not less than −100° C. but not more than100° C., preferably not less than −40° C. but not more than 40° C., morepreferably not less than −20° C. but not more than 25° C. In thetemperature range described above, it is possible to successfully obtainthe iodine cation. The amount of electricity for the electrolysis ispreferably not less than 0.5 F but not more than 5.0 F, per 1 mol of theiodine molecules. This makes it possible to obtain a solution containingthe iodine cation (hereinafter, referred to as an “iodine cationsolution”, in some cases) in the room for the anode. In a case where theamount of electricity is less than 0.5 F, it is impossible to carry outthe electrolysis, and in a case where the amount of electricity is morethan 5.0 F, there is a risk that the solvent is oxidized apart fromiodine, or the iodine cation is excessively oxidized, for example.

Examples of the electrode include: a metal (copper, silver, gold, orplatinum, for example) electrode; an electrode coated with a metal(copper, silver, gold, or platinum, for example); a corrosion-resistingalloy electrode (stainless steel, or HASTELLO® for example); and acarbon electrode (graphite, or diamond, for example). A platinumelectrode is particularly preferable.

1-3. Production of Aromatic Iodine Compound

The iodine cation obtained in the reaction described above can be usedto iodize various compounds. Particularly, the iodine cation is suitablefor use as an iodizing agent for causing iodine to be bound to a nucleusof an aromatic compound.

The following description explains an example of iodization with the useof the iodine cation. In the example, the iodine cation and an aromaticcompound are caused to react with each other in a solvent so as toproduce an aromatic iodine compound. This reaction can be represented bythe following Reaction Formula (5). Reaction Formula (5) is for a casewhere toluene is used as the aromatic compound.

The aromatic iodine compound can be obtained in such a manner that (i)an iodine cation solution is added to a solution in which an aromaticcompound is dissolved, and (ii) the resultant solution is agitated untilthe reaction is completed. In the present invention, the aromaticcompound means a compound showing an aromatic character, and may haveeither an isocyclic ring or a heterocyclic ring. The aromatic compoundhaving the isocyclic ring may be a C₆₋₁₂ compound, such as a benzenering, and a naphthalene ring.

The aromatic compound having the heterocyclic ring may be a compoundhaving a five-membered or six-membered hetero ring having at least one(generally one to three) hetero atom selected from the group consistingof an oxygen atom, a nitrogen atom, and a sulfur atom, for example. Inthis case, the hetero ring may constitute a fused ring. Specifically,examples of the compound having the heterocycle encompass: a compoundcontaining an oxygen atom as a hetero atom (furans, for example); acompound containing a sulfur atom as a hetero atom (thiophenes,thiazoles, or isothiazoles, for example); and a compound containing anitrogen atom as a hetero atom (pyrroles, pyrazoles, imidazoles,triazoles, or pyridines, for example).

Specifically, examples of the aromatic compound include: toluene;ethylbenzene; propylbenzene; isopropylbenzene; tert-butylbenzene;o-xylene; m-xylene; p-xylene; biphenyl; naphthalene; m-terphenyl;p-terphenyl; phenol; anisole; thiophene; aniline; chlorobenzene;bromobenzene; iodobenzene; p-chlorotoluene; o-chlorotoluene;p-chlorophenol; 4-methylanisole; 2 -methylanisole; o-dimethoxybenzene;m-dimethoxybenzene; and p-dimethoxybenzene.

In this case, the solvent for dissolving the aromatic compound may be:acetonitrile; propionitrile; butyronitrile; isobutyronitrile;valeronitrile; isovaleronitrile; pivalonitrile; hexane;methylcyclohexane, heptane; octane; decane; dodecane; methanol; ethanol;propanol; isopropanol; butanol; isobutanol; tert-butanol; diethyl ether;diisopropyl ether; tert-butylmethyl ether; dibutyl ether;cyclopentylmethyl ether; 1,2-dimethoxyethane; 1,2-diethoxyethane;diethylene glycol dimethyl ether; diethylene glycol diethyl ether;diethylene glycol monomethyl ether; diethylene glycol monoethyl ether;triethylene glycol monomethyl ether; triethylene glycol monoethyl ether;tetraethylene glycol dimethyl ether; tetraethylene glycol diethyl ether;tetraethylene glycol monomethyl ether; tetraethylene glycol diethylether; ethylene glycol; ethylene glycol monomethyl ether; ethyleneglycol monoethyl ether; polyethylene glycol; tetrahydrofuran;1,4-dioxane; tetrahydropyran; dichloromethane; chloroform; carbontetrachloride; 1,2-dichloroethane; 1,1,1-trichloroethane;1,1,2-trichloroethane; nitromethane; and pentafluorobenzoic acid, forexample.

Further, in this synthesis, it is possible to improve selectivity of thebinding position of iodine by causing the iodine cation and an aromaticcompound whose nucleus has at least one substituent group and at leasttwo hydrogen atoms, to react with each other under the presence of acertain ether compound.

The aromatic compound may have an electron-donating substituent group.Examples of such an aromatic compound include: toluene; o-xylene;m-xylene; 2-chlorotoluene; 3-methoxyphenol; 2-methylanisole;3-methylanisole; ethylbenzene; cumene; and tert-butylbenzene.

It is considered that an ether compound and an amide compound play arole of sterically preventing iodine from being bound in anortho-position in a solvent. In this case, the ether compound and theamide compound may be added to a solution in which the aromatic compoundis dissolved, or, in a case where the aromatic compound is soluble inthe ether compound and the amide compound, the ether compound and theamide compound themselves may be used as the solvent.

The ether compound may be either an acyclic ether compound or a cyclicether compound. The acyclic ether compound used in the method of thepresent invention, for producing the aromatic iodine compound, includesat least two ether-bonds, and has a carbon chain having 2 or more carbonatoms, between an oxygen atom at one ether bond, and an oxygen atom atanother ether bond. An example of such an acyclic ether compound may bea compound represented by the following General Formula (6)

(where: m is an integer not less than 1; n is an integer not less than2; R¹ and R⁴ are, identically or differently, a hydrogen atom or a C₁₋₃alkyl group; the alkyl group may be substituted by an alkoxy group; R²and R³ are, identically or differently, a hydrogen atom or a C₁₋₃ alkylgroup).

Specifically, examples of the compound represented by General Formula(6) encompass: 1,2-dimethoxyethane; 1,2-diethoxyethane; diethyleneglycol dimethyl ether; diethylene glycol diethyl ether; diethyleneglycol monomethyl ether; diethylene glycol monoethyl ether; triethyleneglycol dimethyl ether; triethylene glycol diethyl ether; triethyleneglycol monomethyl ether; triethylene glycol monoethyl ether;tetraethylene glycol dimethyl ether; tetraethylene glycol diethyl ether;tetraethylene glycol monomethyl ether; tetraethylene glycol monoethylether; ethylene glycol; ethylene glycol monomethyl ether; ethyleneglycol monoethyl ether; and polyethylene glycol.

The cyclic ether compound is a cyclic compound having one or more etherbonds. The cyclic ether compound may be tetrahydrofuran; crown ether;1,4-dioxane; tetrahydropyran; or 1,3,5-trioxane, for example.

Further, in a case where the ether compound is added, an amount of theether compound added to the solution is preferably not less than 0.1times but not more than 10.0 times more than the iodine cation solution,more preferably not less than 0.5 times but not more than 1.5 times morethan the iodine cation solution. In a case where the amount is toosmall, there is no improvement in selectivity, and in a case where theamount is too large, there is a reduction in yield of iodization.

The iodine cation solution obtained by the electrolysis is added to asolution in which the aromatic compound is dissolved, and the resultantsolution is continuously agitated. In this manner, the reaction can becompleted. At this point, the reaction preferably takes place at atemperature of not less than −40° C. but not more than 150° C. Areaction solution thus obtained is subjected to a known separationoperation (extract operation, liquid separation operation), so that atarget reaction product is isolated.

The method of the present invention, for producing an iodizing agent,employs an acid as the supporting electrolyte. Therefore, in a casewhere an iodine compound is synthesized by using the iodine cation as aniodizing agent, it is possible to easily separate the supportingelectrolyte from a reaction solution after reaction is completed. Theinventors of the present invention found, as a result of diligent study,that in place of salt, an acid can be used in electrolyzing iodinemolecules. With the use of an acid, it is not necessary to carry outseparation process by the column chromatography, and an acid can beremoved by, for example, neutralization reaction. For this reason, withthe present invention, it is possible to obtain an iodine cation thatdoes not require a sophisticated separation operation after reaction iscompleted in a case where the iodine cation is used as an iodizingagent.

[2. Method of Producing Aromatic Iodine Compound]

The following description explains details of the method of the presentinvention, for producing an aromatic iodine compound. The method of thepresent invention, for producing an aromatic iodine compound, includesthe step of causing an iodizing agent and an aromatic compound whosenucleus has one or more substituent groups and two or more hydrogenatoms, to react with each other under the presence of a certain ethercompound.

2-1. Iodizing Agent

First, the following description explains the iodizing agent. Theiodizing agent is preferably an iodine cation, for example.

Here, the following description explains a method of producing theiodine cation. The iodine cation can be obtained by, for example,electrolyzing at least one selected from the group consisting of iodinemolecules and an iodine metal compound (iodine anion) in a solutioncontaining a supporting electrolyte. In order to obtain such an iodinecation, firstly, the electrolyte is prepared. The electrolyte is asolution containing (i) a supporting electrolyte, and (ii) iodinemolecules or an iodine metal compound.

(Solvent)

A solvent constituting the electrolyte is a solvent that can dissolve(i) iodine molecules or an iodine metal compound, and (ii) a supportingelectrolyte, so as to contribute to the electrolysis. Such a solvent ispreferably an organic solvent. The organic solvent may be one selectedfrom the group consisting of aliphatic nitrile, alcohol, a chlorinatedsolvent, aliphatic amide, cyclic ether, and nitromethane. Specifically,examples of the organic solvent encompass: acetonitrile; propionitrile;butyronitrile; isobutyronitrile; valeronitrile; isovaleronitrile;pivalonitrile, hexanenitrile; methanol; ethanol; propanol; isopropanol;butanol; isobutanol; tert-butanol; chloroform; dichloromethane; carbontetrachloride; 1,2-dichloroethane; 1,1,1-trichloroethane;1,1,2-trichloroethane; N,N-dimethylformamide; N,N-dimethylacetamide;N-methylpyrrolidone; N-methylpiperidone; tetrahydrofuran; 1,3-dioxane;1,4-dioxane; 1,3,5-trioxane; tetrahydropyran; and nitromethane.

(Supporting Electrolyte)

The supporting electrolyte is preferably an acid or salt. The supportingelectrolyte becomes dissociated into ions in the solvent, and plays arole of introducing electricity to the solvent. In a case where salt isused, examples of the supporting electrolyte include: (nBu)₄NBF₄;Et₄NBF₄; NaClO₄; LiBF₄; LiClO₄; (nBu)₄NClO₄; Et₄NClO₄; LiCl;(nPr)₄NClO₄; Mg(ClO₄)₂; (nBu)₄NCl; (nBu)₄NBr; (nBu)₄NI; Et₄NCl; Et₄NBr;Et₄NI; (nPr)₄NBr; (nPr)₄NI; and KOH.

In a case where an acid is used, the supporting electrolyte may be atleast one selected from the group consisting of sulfuric acid,methanesulphonic acid, benzenesulphonic acid, p-toluenesulphonic acid,and phosphoric acid. The supporting electrolyte is preferably an acid.With the use of an acid, there is an advantage that it is unnecessary tocarry out the separation operation by the column chromatography, in acase where the supporting electrolyte is removed after the iodizingreaction is completed.

In the case of an acid, a concentration of the acid in the electrolyteis not less than 0.01 mol/L but not more than 19.0 mol/L, preferably notless than 0.05 mol/L but not more than 10.0 mol/L, more preferably notless than 0.1 mol/L but not more than 5.0 mol/L. In a case where theconcentration of the acid is lower than 0.01 mol/L, it is impossible tocause the electricity to flow in the solution. That is, the acid cannotplay the role of the supporting electrolyte. Further, in a case wherethe concentration of the acid is higher than 19.0 mol/L, there is aproblem that it is difficult to prepare the concentration of the acid.

(Iodine Molecules or Iodine Metal Compound)

In the method of the present invention, for producing the iodine cation,the iodine molecules or the iodine metal compound is electrolyzed. In acase where the iodine molecules are used, a content ratio of the iodinemolecules in the electrolyte is not less than 0.1 percent by mass butnot more than 50 percent by mass, preferably not less than 0.5 percentby mass but not more than 25 percent by mass, more preferably not lessthan 1.0 percent by mass but not more than 10 percent by mass. In a casewhere an amount of the iodine molecules in the electrolyte is within therange described above, the iodine cation can be successfully producedwithout a reduction in productivity. Examples of the iodine metalcompound include: potassium iodide; sodium iodide; lithium iodide;ammonium iodide; barium iodide; copper iodide; lead iodide; and rubidiumiodide.

A starting compound for obtaining the iodine cation is preferably theiodine molecules. Unlike the iodine metal compound, the iodine moleculesdo not exist as an ion in the solvent. Therefore, with the use of theiodine molecules, it is possible to generate the iodine cation byextracting only one electron. On the other hand, since the iodine metalcompound exists as a monovalent iodine anion in the solvent, it isnecessary to extract two electrons in order to obtain the iodine cationwith the use of the iodine metal compound. In other words, there is anadvantage that, by electrolyzing the iodine molecules, the amount ofelectricity becomes less required for the electrolysis. Further, if theiodine metal compound (sodium iodide, or potassium iodide, for example)is used as the starting compound, a metal ion is mixed with a resultantiodine cation solution. However, if the iodine molecules are used as thestarting compound, it is possible to avoid such a state. Therefore, itis possible to obtain the iodine cation that does not require separationoperation employing the column chromatography.

(Electrolysis).

The electrolysis is carried out with the use of the electrolytedescribed above, so as to obtain the iodine cation in accordance withthe following Reaction Formula (4). The following Reaction Formula (4)is for a case where the iodine molecules are oxidized by theelectrolysis.

This electrolysis can be carried out, for example, with the use of anelectrolytic cell in which two rooms are provided for the anode and thecathode, respectively and independently. Into the room for the anode,the iodine molecules or the iodine metal compound are/is provided, andinto the room for the cathode, the supporting electrolyte and thesolvent are provided. Further, the reaction can be carried out at atemperature of not less than −100° C. but not more than 100° C.,preferably at a temperature of not less than −40° C. but not more than40° C., more preferably at a temperature of not less than −20° C. butnot more than 25° C. The iodine cation can be successfully obtained at atemperature in the range described above. The amount of the electricityused in the electrolysis is preferably not less than 0.5 F but not morethan 5.0 F, per 1 mol of the iodine molecules. This makes it possible toproduce a solution containing the iodine cation (hereinafter, referredto as “iodine cation solution” in some cases) in the room for the anode.In a case where the amount of the electricity is less than 0.5 F, it isimpossible to carry out the electrolysis, and in a case where the amountof the electricity is more than 5.0 F, there is a risk that the solventapart from iodine is oxidized, or the iodine cation is excessivelyoxidized, for example.

Examples of the electrode include: a metal electrode (copper, silver,gold, or platinum, for example); an electrode coated with a metal(copper, silver, gold, or platinum, for example); a corrosion-resistingalloy electrode (stainless steel, or HASTELLOY®, for example); and acarbon electrode (graphite, or diamond, for example). The platinumelectrode is particularly preferable.

In addition to the aforementioned method of producing the iodine cationby carrying out the electrolysis, the following method can be used toobtain the iodine cation. At least one selected from the groupconsisting of N-iodosuccinimide, N,N-diiodo-5,5-dimethylhydantoin, andbispyridineiodonium tetrafluoroborate is dissolved in the solvent, andan acid (such as tetrafluoroboric acid or trifluoromethansulphonic acid)is added to the resultant solution. This makes it possible to easilyproduce the iodine cation.

Further, other than the acids described above, an oxidizing agent may beadded to the resultant solution so as to produce the iodine cation.Examples of the oxidizing agent encompass: sodium hypochlorite, sodiumchlorite, sodium chlorate, sodium perchlorate, sodium hypobromite,sodium bromate, sodium periodate, sodium iodate, chlorine, bromine,ammonium persulfate, hydrogen peroxide, and acetyl hydroperoxide.

2-2. Production of Aromatic Iodine Compound

Next, the iodine cation obtained by the electrolysis and an aromaticcompound having one or more substituent groups are caused to react witheach other. The following description explains a method of the presentinvention, for producing an aromatic iodine compound. The explanationsare made for a case where the aromatic compound is toluene, for example.

The aromatic iodine compound of the present invention is produced inaccordance with the following Reaction Formula (5):

An aromatic compound used here has a nucleus to which one or moresubstituent groups and two or more hydrogen atoms are bound. In thepresent invention, the aromatic compound is a compound showing anaromatic characteristic, and may have either an isocyclic ring or aheterocyclic ring (nucleus). The aromatic compound having the isocyclicring may be, for example, a compound having a C₆₋₁₂ isocyclic ring, suchas a benzene ring, or a naphthalene ring.

The aromatic compound having the heterocyclic ring may be, for example,a compound having a five-membered or six-membered heterocycle having atleast one (generally one to three) hetero atom selected from the groupconsisting of an oxygen atom, a nitrogen atom, and a sulfur atom. Inthis case, the heterocycle may constitute a fused ring. Specifically,examples of the compound having the heterocycle encompass: furans eachof which includes an oxygen atom as the hetero atom; thiophenes each ofwhich includes a sulfur atom as the hetero atom; thiazoles each of whichincludes a sulfur atom as the hetero atom; isothiazoles each of whichincludes a sulfur atom as the hetero atom; pyrroles each of whichincludes a nitrogen atom as the hetero atom; pyrazoles each of whichincludes a nitrogen atom as the hetero atom; imidazoles each of whichincludes a nitrogen atom as the hetero atom; triazoles each of whichincludes a nitrogen atom as the hetero atom; and pyridines each of whichincludes a nitrogen atom as the hetero atom.

Specifically, the aromatic compound preferably has one or moresubstituent groups. The substituent group is preferably anelectron-donating group, in particular. Examples of such an aromaticcompound encompass: toluene; o-xylene; m-xylene; fluorobenzene;chlorobenzene; iodobenzene; phenol; o-cresol; m-cresol; anisole;aniline; N,N-dimethyaniline; o-toluidine; m-toluidine; 2-chlorotoluene;3-chlorotoluene; 2-bromotoluene; 3-bromotoluene; 2-fluorotoluene;3-fluorotoluene; 2-iodotoluene; 3-iodotoluene; 2-methoxyphenol;3-methoxyphenol; 2-methylanisole; 3-methylanisole; 1,2-dimethoxybenzene;1,3-dimethoxybenzene; ethylbenzene; propylbenzene; benzyl chloride;benzyl bromide; cumene; tert-butylbenzene; biphenyl; and p-terphenyl.

In this case, the solvent for dissolving the aromatic compound may be:acetonitrile; propionitrile; butyronitrile; isobutyronitrile;valeronitrile; isovaleronitrile; pivalonitrile; hexane;methylcyclohexane; heptane; octane; decane; dodecane; methanol; ethanol;propanol; isopropanol; butanol; isobutanol; tert-butanol; diethyl ether;diisopropyl ether; tert-butylmethyl ether; dibutyl ether;cyclopentylmethyl ether; 1,2-dimethoxyethane; tetrahydrofuran;1,4-dioxane; tetrahydropyran; dichloromethane; chloroform; carbontetrachloride; 1,2-dichloroethane; 1,1,1-trichloroethane;1,1,2-trichloroethane; nitromethane; and pentafluoro benzoic acid.Further, the solvent may be an ether compound (which will be describedlater).

In the present invention, the reaction between the iodizing agent andthe aromatic compound takes place under the presence of a certain ethercompound. The certain ether compound presumably plays a role ofinhibiting iodine from being bound in the ortho-position in the solvent.In the present invention, the certain ether compound may be added to asolution in which the aromatic compound is dissolved, or, in a casewhere the aromatic compound is soluble in the certain ether compound,the certain ether compound itself may be used as the solvent.

(Ether Compound)

The ether compound may be at least one selected from the groupconsisting of cyclic or acyclic ether compounds being represented byGeneral Formula (3):

(where: m is any integer in a range from 2 to 6; n is an integer notless than 1; R¹ and R² are, identically or differently, a hydrogen atomor a C₁₋₁₀ alkyl group; R³ and R⁴ are, identically or differently, ahydrogen atom or a C₁₋₁₀ alkyl group).

Specifically, examples of the ether compound represented by GeneralFormula (3) encompass: 1,2-dimethoxyethane; 1,2-diethoxyethane;diethyleneglicoldimethyl ether; diethyleneglicoldiethyl ether;diethyleneglicolmonomethyl ether; diethyleneglicolmonoethyl ether;triethyleneglicolmonomethyl ether; triethyleneglicolmonoethyl ether;triethyleneglicoldimethyl ether; triethyleneglicoldiethyl ether;tetraethyleneglicoldimethyl ether; tetraethyleneglicoldiethyl ether;tetraethyleneglicolmonomethyl ether; tetraethyleneglicolmonoethyl ether;ethyleneglicol; ethyleneglicolmonomethyl ether; ethyleneglicolmonoethylether; and polyethyleneglicol.

The cyclic ether compound is a cyclic compound having one or more etherbonds. Examples of the cyclic ether compound encompass: ethylene oxide;triethylene oxide; tetrahydrofuran; crown ether; 1,4-dioxane;1,3-dioxane; tetrahydropyran; and 1,3,5-trioxane.

Further, in a case where the ether compound is added to the solution, anamount of the ether compound added to the solution is preferably 0.1 to10.0 times more than a content of the iodizing agent solution, morepreferably 0.5 to 1.5 times more than the content of the iodizing agentsolution. In a case where the amount is less than 0.1 times the iodizingagent solution, there is no improvement in selectivity, and in a casewhere the amount is more than 10.0 times the iodizing agent solution,there may be a reduction in yield of the iodization.

To the solution in which the aromatic compound is dissolved, the iodinecation solution obtained by the electrolysis is added, and the resultantsolution is agitated continuously. Thereby, the reaction is completed.At this time, the reaction preferably takes place at a temperature ofnot less than −40° C. but not more than 100° C. The resultant reactionsolution is subjected to the separation operation (extract operation,liquid separation operation), so as to isolate the target reactionproduct. Further, the reaction preferably takes place at a temperatureof not less than −40° C. but not more than 0° C. By carrying out thereaction at a temperature in the range, the position selectivity can befurther improved.

After that, the reaction product is isolated by a known separationoperation (extracting, liquid separating, or the column chromatography,for example).

Further, it is possible to increase a degree of purity of the reactionproduct thus obtained by recrystallizing the reaction product.Specifically, it is preferable that (i) the resultant crude product isdissolved in an alcohol (such as methanol, ethanol, propanol,isopropanol, and butanol), (ii) deposition of a crystal is carried outat a temperature of not less than −80° C. but not more than 0° C., andthen (iii) this procedure is repeated several times. With this method,it is possible to increase the degree of purity to approximately 98%. Bycarrying out the process within the temperature range, it is possible tocarry out the recrystallization to obtain a high purity product.

Further, the operation to increase the degree of purity of the productis not limited to the recrystallization, and a high purity reactionproduct can be isolated by carrying out distillation process withrespect to the resultant reaction solution.

According to the method of the present invention, for producing anaromatic iodine compound, it is possible to improve selectivity of abinding position of iodine by causing, in iodizing process, an iodinecation and an aromatic compound to react with each other under thepresence of a certain ether compound. Therefore, it becomes possible toefficiently produce the target aromatic iodine compound.

Further, the certain ether compound used in the method of the presentinvention, for producing an aromatic iodine compound, is stable in asolvent, so that it is easy to handle the certain ether compound.Therefore, it is possible to carry out, with high reproducibility, theiodizing reaction in which position selectivity is improved. Thereby itis possible to provide a production method suitable forindustrialization.

Furthermore, the method of the present invention, for producing anaromatic iodine compound, has an advantage that, by using, as aniodizing agent, the iodine cation obtained by electrolysis for which anacid is used as a supporting electrolyte, the supporting electrolyte canbe removed easily after the reaction is completed.

EXAMPLES

The following description explains examples of the present invention. Itshould be noted that the present invention is not limited to thefollowing examples.

[1. Production of Iodizing Agent]

Example 1

(Production of Iodine Cation)

Production of an iodine cation was carried out with the use of an H-type2-room electrolytic cell under an anhydrous condition. At that time, aglass filter (G4) was used as a diaphragm. As an anode electrode and acathode electrode, platinum plates (30 mm×20 mm) were used. Theelectrolytic cell was dried under reduced pressure, and then was filledwith nitrogen atmosphere. Then, 13 mL of an acetonitrile solutioncontaining 2.0M of sulfuric acid was provided in a cathode room, and 13mL of acetonitrile solution containing 2.0M of sulfuric acid, and 127 mg(0.500 mmol) of iodine were provided in an anode room. After that, theelectrolytic cell was cooled down to 0° C. While the anode room and thecathode room were agitated with the use of a magnetic stirrer,electrolysis was carried out with a constant current (20 mA) at 0° C. Byapplying 2.0 F/mol electricity, an iodine cation solution was obtainedfrom the anode room.

(Production of Aromatic Iodine Compound)

Next, 12.5 ml of the iodine cation solution thus obtained was added to2.5 ml of an acetonitrile solution containing 92 mg (1.0 mmol) oftoluene. At this point, a temperature of a reaction solution was 0° C.The reaction solution was agitated for a half hour. After reaction wascompleted, 13 mL of 4N aqueous sodium hydroxide was added to thereaction solution at 0° C., so as to neutralize the reaction solution.Then, the resultant solution was diluted with 20 mL of ether. Aresultant reaction mixture was put into a separatory funnel, so that themixture was separated into an organic layer and an aqueous layer. Theaqueous layer was extracted with ether, and the organic layer was washedwith a saturated saline. The organic layer was dehydrated with magnesiumsulfate, and was filtered. A filtrate thus obtained was concentratedunder reduced pressure, and the resultant reaction solution wasconcentrated under reduced pressure. Thereby, a dry substance in which4-iodotoluene (referred to as “4-I body” in Table 1) and 2-iodotoluene(referred to as “2-I body” in Table 1) were mixed together was obtained.Table 1 shows a yield of the resultant reaction product and a mixtureratio of the 4-iodotoluene and 2-iodotoluene.

Example 2

In Example 2, production of an iodine cation was carried out in the samemanner as Example 1, except that 5.0 mol/L of a methanesulphonic acidsolution was used as the supporting electrolyte. As a result, anaromatic iodine compound was obtained. Table 1 shows a yield of theresultant reaction product and a mixture ratio of 4-iodotoluene and2-iodotoluene.

Example 3

In Example 3, production of an iodine cation was carried out in the samemanner as Example 1, except that 4.0 mol/L of a phosphoric acid solutionwas used as the supporting electrolyte. As a result, an aromatic iodinecompound was obtained. Table 1 shows a yield of the resultant reactionproduct and a mixture ratio of 4-iodotoluene and 2-iodotoluene.

Example 4

In Example 4, production of an iodine cation was carried out in the samemanner as Example 1, except that 2.0 mol/L of trifluoromethanesulphonicacid was used as the supporting electrolyte, and electrolysis wascarried out at −20° C. As a result, an aromatic iodine compound wasobtained. Table 1 shows a yield of the resultant reaction product and amixture ratio of 4-iodotoluene and 2-iodotoluene.

Example 5

In Example 5, production of an iodine cation was carried out in the samemanner as Example 1, except that 2.0 mol/L of benzenesulphonic acid wasused as the supporting electrolyte. As a result, an aromatic iodinecompound was obtained. Table 1 shows a yield of the resultant reactionproduct and a mixture ratio of 4-iodotoluene and 2-iodotoluene.

Comparative Example 1

In Comparative Example 1, reaction was carried out in the same manner asExample 1, except that 4.59 mol/L of trifluoroacetic acid was used asthe supporting electrolyte. However, a current did not flow even when avoltage up to 110V was applied. For this reason, iodine molecules werenot electrolyzed, and an iodine cation solution could not be obtained.

TABLE 1 Supporting Electrolyte Solvent Yield (%) 4-I/2-I Example 1 H₂SO₄CH₃CN 87.2 55/45 Example 2 MeSO₃H CH₃CN 67.0 56/44 Example 3 H₃PO₄ CH₃CN32.0 67/33 Example 4 CF₃SO₃H CH₃CN 61.8 70/30 Example 5 C₆H₅SO₃H CH₃CN42.3 62/38 Comparative CF₃COOH CH₃CN — Example 1

In Examples 1 through 5, it was possible to produce iodotoluene bycausing a solution obtained by electrolysis and toluene to react witheach other. From the results, it was confirmed that the iodine cationwas produced by the electrolysis in Examples 1 through 5.

Example 6

A solution containing an iodine cation was produced in the same manneras Example 1. To 12.5 ml of the iodine cation solution, 10 ml of1,2-diethoxyethane was added. Then, 92 mg (1.0 mmol) of toluene and 2.5ml of 1,2-dimethoxyethane were provided in a 50 ml eggplant-shapedflask, agitated with the use of a magnetic stirrer, and cooled down to0° C. in an ice bath. Into the flask, 22.5 ml of the iodine cationsolution was added, and left for one hour at 0° C. The resultantreaction solution was concentrated under reduced pressure, and thendried. Thereby a reaction product was obtained. The reaction productthus obtained was 4-iodotoluene and 2-iodotoluene. A yield of thereaction product was 79.8%, and a mixture ratio of 4-iodotoluene and2-iodotoluene was 73:27.

From a result of Example 6, it was confirmed that, by using, as asolvent of iodizing reaction, diethoxyethane that is an ether compound,an aromatic iodine compound in which iodine was bound in a para-positionwas produced with high productivity.

Example 7 through Example 29

In Examples 7 through 29, an aromatic iodine compound was obtained inthe same manner as Example 1, except that an aromatic compound wasreplaced with a compound shown in Table 2.

TABLE 2 Aromatic Product Compound Ratio of Example (Substrate) YieldAr-1 Isomers 7

85.6^(c)

 71/29 8

89.7^(c)

 86/14 9

91.3^(c)

96/4 10

82.3^(f)

96/4 11

79.4^(c,g)

93/7 12

63.7^(e)

— 13

56.0^(b)

93/7

14

72.4^(b)

93/7

15

16.3^(b)

— 16

51.7^(b)

— 17

9.7^(b)

92/8 18

26.6^(f)

 83/17 19

12.4^(e)

 79/21 20

21.0^(f)

 72/28 21

22.1^(b)

— 22

69.2^(a)

— 23

86.9^(e)

 83/17 24

86.3^(e)

93/7 25

27.3^(e)

 68/32 26

45.7^(e)

60/8/26/7

27

62.0^(e)

— 28

82.0^(e)

— 29

91.4^(e)

— ^(a)based on I₂. ^(b)GC Yield. ^(c)isolated yield. ^(d)mixture ofregloisomer. ^(e)determined by ¹H—NMR analysis. ^(f)2.2 eq. of “I⁺” wasused. gbased on substrate.

As shown in Table 2, it was confirmed that, according to presentexamples, it is possible to successfully obtain an aromatic iodinecompound with the use of the iodine cation.

Example 30 through Example 42

(Production of Iodine Cation)

With the use of the same device as in Example 1, 56 ml of anacetonitrile solution containing 2.0M of sulfuric acid was provided in acathode room, and 56 ml of an acetonitrile solution containing 2.0M ofsulfuric acid, and 1.524 g (6 mmol) of iodine molecules were provided inan anode room. Then, the device was cooled down to 0° C. While thecathode room and the anode room were agitated with the use of a magneticstirrer, a 20 mA current was caused to flow in the device at 0° C. so asto carry out electrolysis. By applying 2.0 F/mol of electricity, aniodine cation solution was obtained from the anode room. The iodinecation solution thus obtained was put in an eggplant-shaped flask, andleft in a constant-temperature bath at −20° C.

(Production of Aromatic Iodine Compound)

After the iodine cation solution was obtained in the method describedabove, 2 ml (approximately 0.12M, 0.42 mmol) of the iodine cationsolution was taken by use of a syringe, and a solvent shown in Table 3was added to the iodine cation solution thus taken. Then the iodinecation solution was added, via a cannula, into a flask in which 77.4 mg(0.84 mmol) of toluene was provided in advance. Reaction took place for30 minutes at 0° C. After the reaction was completed, the solution wasneutralized with an aqueous sodium hydroxide. Then, ether was added tothe solution, so that an aqueous layer was extracted. After being washedwith a supersaturated salt solution once, an ether layer was dried withmagnesium sulfate, and filtered. A filtrate thus obtained was subjectedto gas chromatograph analysis (internal reference method). The followingTable 3 shows a yield of the resultant product (4-iodotoluene and2-iodotoluene) and a mixture ratio of 4-iodotoluene and 2-iodotoluene.

TABLE 3 Amount Yield of solvent Constant Ratio Solvent (ml) (%)(4-I/2-I) Example 30 Propionitrile 2.0 90.9 57/43 Example 31Isobutyronitrile 2.0 68.4 56/44 Example 32 1,1,1-trimethoxyethane 2.022.9 76/24 Example 33 1,1,1-trimethoxy-2- 0.3 79.7 62/38 methylpropaneExample 34 Diethyl ether 2.0 88.7 64/36 Example 35 Diisopropyl ether 2.015.0 59/41 Example 36 Methanol 1.0 32.0 68/32 Example 37 Ethanol 2.010.9 67/33 Example 38 Propanol 2.0 23.3 63/37 Example 39 Butanol 2.038.1 63/37 Example 40 Pentafluoro acetic acid 0.7 84.1 54/46 Example 4170% Phosphoric acid 1.0 37.1 63/37 aqueous solution Example 42Dichloromethane 2.0 50.9 55/45

From results of Examples 30 through 42, it was confirmed that, even in acase where various solvents are used, an aromatic compound can beiodized.

[Production of Aromatic Iodine Compound]

Example 43

(Production of Iodine Cation)

Production of an iodine cation was carried out with the use of an H-type2-room electrolytic cell under an anhydrous condition. At that time, aglass filter (G4) was used as a diaphragm. As an anode electrode and acathode electrode, platinum plates (30 mm×20 mm) were used. Theelectrolytic cell was dried under reduced pressure, and was filled withnitrogen atmosphere. Then, 8 mL of an acetonitrile solution in which 79mg (0.526 mmol) of trifluoromethanesulphonic acid and 0.3M oftetrabutylammoniumtetrafluoroborate (supporting electrolyte) weredissolved was provided in a cathode room, and 8 mL of an acetonitrilesolution in which 0.3M tetrabutylammoniumtetrafluoroborate (supportingelectrolyte) was dissolved and 127 mg (0.500 mmol) of iodine wereprovided in an anode room. After that, the electrolytic cell was cooleddown to 0° C. While the anode room and the cathode room were agitatedwith the use of a magnetic stirrer, electrolysis was carried out with aconstant current (20 mA) at 0° C. By applying 2.0 F/mol of electricity,an iodine cation solution was obtained from the anode room.

(Production of Aromatic Iodine Compound)

Next, 92 mg (1.0 mmol) of toluene which is an aromatic compound havingone substituent group and 8 ml of 1,2-dimethoxyethane which is anacyclic ether compound were provided in a 50 ml eggplant-shaped flask,agitated with the use of a magnetic stirrer, and cooled down to 0° C. inan ice bath. Into the flask, 12.5 ml of the iodine cation solutionobtained by the electrolysis was added, and reaction took place for onehour at 0° C. The resultant reaction solution thus obtained wasconcentrated under reduced pressure, and was put in a 10 cm silica gelcolumn, so as to cause a resultant reaction product to be dissolved outfrom the column with the use of 100 ml of ether. A solvent wasconcentrated under reduced pressure, and 100 ml of a saturated sodiumhydrogen carbonate solution and 50 ml of hexane were added to thereaction product. Thereby, extraction was carried out. After liquidseparation process was carried out, a hexane layer was concentratedunder reduced pressure, and the reaction product was dried. The reactionproduct thus obtained was a mixture of 4-iodotoluene and 2-iodotoluene.The following Table 4 shows a yield and a ratio of the reaction product.It should be noted that in Table 4, a product in which iodine is boundin a para-position is referred to as “I”, and a product in which iodineis bound in an ortho position is referred to as “II”. Further, the ratiowas determined from a measurement result of ¹H-NMR.

(Recrystallization)

The reaction product thus obtained was dissolved in 0.7 ml of methanol,and a crystal was separated out at −40° C. This operation was carriedout twice, so that a reaction product in which a degree of purity of4-iodotoluene was 98% was obtained.

Example 44 through Example 48

(Production of Iodine Cation)

In a cathode room of an electrolytic cell, 8 mL of an acetonitrilesolution containing 2.0M of sulfuric acid was provided, and in an anoderoom of the electrolytic cell, 8 mL of an acetonitrile solutioncontaining 2.0M of sulfuric acid, and 127 mg (0.50 mmol) of iodinemolecules were provided. While the anode room and the cathode room wereagitated with the use of a magnetic stirrer, electrolysis was carriedout with a constant current (20 mA) at 25° C. Then 2.0 F/mol ofelectricity was applied. As a result, an iodine cation solution wasobtained.

(Production of Aromatic Iodine Compound)

Next, 92 mg (1.0 mmol) of toluene was dissolved in 3.6 mL of1,2-dimethoxyethane, and the resultant solution was cooled down to atemperature shown in Table 4. Then, the iodine cation solution thusobtained was added to the solution, and reaction took place for one hourat the temperature of the above cooling process. After the reaction wascompleted, an aqueous sodium hydroxide and ether were added to thesolution, so as to neutralize the solution. The solution was separatedinto an ether layer and an aqueous layer. The ether layer and theaqueous layer were liquid-separated. Then ether was added to the aqueouslayer, so as to liquid-separated the aqueous layer. This operation wascarried out twice. The ether layers thus obtained was mixed together,and was washed with a saturated saline. The resultant product wasconcentrated under reduced pressure. Thereby a dried product wasobtained. The resultant product thus obtained was 4-iodotoluene and2-iodotoluene. The following Table 4 shows a yield and a ratio of theproduct.

TABLE 4 Reaction Ratio Ether compound temperature Yield (%) (I/II)Example 43 DME    0° C. 42.4 79/21 Example 44 DME   25° C. 52.1 70/30Example 45 DME    0° C. 73.2 72/28 Example 46 DME −20° C. 75.4 74/26Example 47 DME −30° C. 75.1 75/25 Example 48 DME −40° C. 75.7 77/23Abbreviation: DME stands for 1,2-dimethoxyethane.

Example 49 through Example 52

In Examples 49 through 52, 4-iodotoluene and 2-iodotoluene were obtainedin the same manner as Example 43, except that an ether compound wasreplaced with a compound shown in the following Table 5. The followingTable 5 shows a yield and a ratio of a resultant product.

TABLE 5 Reaction Yield Ratio Ether compound temperature (%) (I/II)Example 49 1,4 dioxane 0° C. 52.4 75/25 Example 50 Tetrahydrofuran 0° C.33.0 75/25 Example 51 Diethyleneglicoldimethyl ether 0° C. 18.0 82/18Example 52 Tetraethyleneglicoldimethyl 0° C. 10.4 75/25 ether

Example 53

(Production of Iodine Cation)

An iodine cation solution was obtained in the same manner as Example 43,except that 13 mL of an acetonitrile solution containing 2.0M ofsulfuric acid (supporting electrolyte) was provided in a cathode room ofan electrolytic cell, and 13 mL of an acetonitrile solution containing2.0M of sulfuric acid, and 127 mg (0.500 mmol) of iodine were providedin an anode room of the electrolytic cell.

(Production of Aromatic Iodine Compound)

Next, 12.5 ml (1.0 mmol) of the iodine cation solution thus obtained wasadded to 10 ml of dimethoxyethane (an acyclic ether compound). Theresultant solution was added to a mixture of 92 mg (1.0 mmol) of tolueneand 2.5 ml of dimethoxyethane, which is an acyclic ether compound. Thenreaction took place. At this point, a temperature of the reaction was 0°C. The solution was agitated for a half hour. After the reaction wascompleted, 13 mL of a 4N aqueous sodium hydroxide was added to thesolution at 0° C., so as to neutralize the solution. Then 20 mL of etherwas added to the solution so as to dilute the solution. A reactionmixture thus obtained was put in a separatory funnel, so that thereaction mixture was separated into an organic layer and an aqueouslayer. The aqueous layer was extracted with ether, and the organic layerwas washed with a saturated saline. The organic layer was dried with theuse of magnesium sulfate, and then was filtered. A filtrate thusobtained was concentrated under reduced pressure, and the resultantreaction solution was concentrated under reduced pressure. As a result,a dried product in which 4-iodotoluene and 2-iodotoluene were mixedtogether was obtained. Table 6 shows a yield of the resultant reactionproduct of Example 53 and a production ratio of 4-iodotoluene and2-iodotoluene.

Example 54 through Example 61

In Examples 54 through 61, an aromatic iodine compound was obtained inthe same manner as Example 53, except that an aromatic compound (astarting compound) was replaced with a compound shown in Table 6. Thefollowing Table 6 shows a yield and a ratio of a resultant product.

Comparative Example 2

In Comparative Example 2, production of an iodine cation was carried outin the same manner as Example 53. Then, an iodine cation solution thusobtained was added to 12.5 ml of an acetonitrile solution containingtoluene. After that, the resultant solution was agitated for one hour.The resultant reaction solution was concentrated under reduced pressure,and thereby a reaction product containing 4-iodotoluene and2-iodotoluene was obtained. The following Table 6 shows a yield and aratio of the resultant product.

Comparative Example 3 through Comparative Example 10

In Comparative Examples 3 through 10, an aromatic iodine compound wasobtained in the same manner as Comparative Example 2, except that anaromatic compound (starting compound) was replaced with anothercompound. The following Table 6 shows a yield of the aromatic iodinecompound and a ratio of a binding position of iodine in the aromaticiodine compound. It should be noted that in Table 6, ComparativeExamples 2 through 10 correspond to Examples 53 through 61 respectively.Results of Comparative Examples are associated with the results of thecorresponding Examples in Table 6.

TABLE 6 Aromatic Product Compound Ratio of (Substrate) Yield (%)^(a,d)isomers Example 53 Comparative example 2

79.8^(c) 87.9^(c)

 73/27  57/43 Example 54 Comparative example 3

82.1^(c) 85.6^(c)

 82/18  71/29 Example 55 Comparative example 4

84.8^(c) 89.7^(c)

91/9  86/14 Example 56 Comparative example 5

89.3^(c) 91.3^(c)

97/3 96/4 Example 57 Comparative example 6

81.0^(e) 86.9^(c)

 88/12  83/17 Example 58 Comparative example 7

82.4^(e) 86.3^(c)

94/6 93/7 Example 59 Comparative example 8

88.8^(b) 56.0^(b)

98/2 93/7 Example 60 Comparative example 9

82.3^(b) 72.4^(b)

97/3 93/7 Example 61 Comparative example 10

12.5^(c) 45.7^(e)

64/7/23/7 60/8/26/7 ^(a)based on I₂. ^(b)GC Yield. ^(c)isolated yield.^(d)mixture of regloisomer. ^(e)determined by ¹H—NMR analysis.

As clearly seen from Tables 4 through 6, it was confirmed that accordingto the method of Examples, for producing an aromatic iodine compound, anaromatic iodine compound in which iodine was bound in a para-positionwas produced with high selectivity. Further, as seen from comparisonsbetween Examples 43 through 48, it was confirmed that the selectivity isimproved as a reaction temperature in iodization becomes low.

Example 62 through Example 73

(Production of Iodine Cation)

In a cathode room of an electrolytic cell, 56 ml of an acetonitrilesolution containing 2.0M of sulfuric acid was provided, and in an anoderoom of the electrolytic cell, 56 ml of an acetonitrile solutioncontaining 2.0M of sulfuric acid, and 1.524 g (6 mmol) of iodinemolecules were provided. Then the electrolytic cell was cooled down to0° C. While the cathode room and the anode room were agitated by amagnetic stirrer, electrolysis was carried out with a constant current(20 mA) at 0° C. By applying 2.0 F/mol of electricity, an iodine cationsolution was obtained from the anode room. The iodine cation solutionthus obtained was put in an eggplant-shaped flask, and then was left ina constant-temperature bath at −20° C.

(Production of Aromatic Iodine Compound)

After the iodine cation solution was obtained by the method describedabove, 2 ml (approximately 0.21M, 0.42 mmol) of the iodine cationsolution was taken with the use of a syringe. Then an ether compound(solvent) shown in Table 7 was added to the iodine cation solution thustaken. After that, the resultant solution was added, via a cannula, intoa flask in which 77.4 mg (0.84 mmol) of toluene was provided in advance.Then reaction took place for a half hour at 0° C. After the reaction wascompleted, the resultant solution was neutralized with the use of anaqueous sodium hydroxide. Then ether was added to the resultantsolution, so as to extract an aqueous layer. An ether layer was washedwith a saturated saline once, dried with the use of magnesium sulfate,and filtered. A filtrate thus obtained was subjected to gaschromatograph analysis (internal reference method). Table 7 shows ayield of the resultant product, and a production ratio of 4-iodotolueneand 2 -iodotoluene.

TABLE 7 Ether compound Yield (%)^(a, b) Ratio (I/II) Example 62 DME (2.0ml) 92.0 71/29 Example 63 DEE (2.0 ml) 91.8 66/34 Example 64 TEGDE (2.0ml) 85.3 67/33 Example 65 1,4-dioxane (1.0 ml) 90.2 66/34 Example 66Diethyleneglicoldimethyl ether 47.5 72/22 (5.0 ml) Example 67Ethyleneglicol (2.0 ml) 49.3 66/34 Example 68 PEG400 (2.0 ml) 65.0 61/39Example 69 Et₂O (2.0 ml) 88.7 64/36 Example 70 i-Pr₂O (2.0 ml) 15.759/41 Example 71 THF (2.0 ml) 68.4 68/32 Example 72 Tetrahydropyran (2.0ml) 72.3 69/31 Example 73 Trimethoxyethane (2.0 ml) 22.9 76/24 ^(a)basedon I₂. ^(b)GC Yield. ^(c)5.0 mL (0.670 mmol) of iodine cation solution.DEE: 1,2-diethoxyethane. TEGDE: tetraethyleneglicoldimethyl ether.

As seen from results shown in Table 7, it was confirmed that even in acase where various ether compounds are used, an aromatic iodine compoundcan be produced successfully.

With the method of the present invention, for producing an iodizingagent, an iodine cation can be produced by electrolyzing iodinemolecules by using an acid as a supporting electrolyte. In a case wherean iodine compound is obtained by use of an iodine cation solution thusobtained, it is unnecessary to carry out a sophisticated separationoperation using column chromatography after reaction is completed.Therefore, it is possible to produce an iodine cation which is suitablyused as an iodizing agent suitable for industrial production of aniodine compound.

Further, according to a method of present invention, for producing anaromatic iodine compound, as described above, it is possible to increaseselectivity of a binding position of an iodine atom with respect to anaromatic compound by causing an iodizing agent and an aromatic compoundhaving one or more substituent groups to react with each other under thepresence of a certain ether compound.

The embodiments and concrete examples of implementation discussed in theforegoing detailed explanation serve solely to illustrate the technicaldetails of the present invention, which should not be narrowlyinterpreted within the limits of such embodiments and concrete examples,but rather may be applied in many variations within the spirit of thepresent invention, provided such variations do not exceed the scope ofthe patent claims set forth below.

INDUSTRIAL APPLICABILITY

A method of the present invention, for producing an iodizing agent, canbe applied to iodization of various compounds, and can be used toproduce an iodine cation which is suitable for industrial production.Further, with a method of the present invention, for producing anaromatic iodine compound, it is possible to produce an aromatic iodinecompound which is suitably used as a reaction intermediate.

1-4. (canceled)
 5. An electrolyte comprising: an acid used as asupporting electrolyte; and iodine molecules, wherein: the supportingelectrolyte contains the acid only; the acid has a concentration of notless than 0.01 mol/L but not more than 19.0 mol/L; the acid is at leastone selected from the group consisting of: sulphonic acids andphosphoric acids, the sulphonic acids are represented by the followingGeneral Formula (1):R¹SO₃H   (1) (where: R¹ is one selected from the group consisting of ahydroxyl group, a C₁₋₆ alkyl group, a phenyl group, and a naphthylgroup; in the alkyl group, a hydrogen atom may be substituted with afluorine atom; the phenyl group and the naphthyl group may have asubstituent group); and the phosphoric acids being represented by thefollowing General Formula (2):

(where: R² and R³ are identically or differently a hydrogen atom, aC₁₋₁₀ alkyl group, or a phenyl group; and the phenyl group may have asubstituent group).
 6. The electrolyte according to claim 5, wherein: aconcentration of the iodine molecules is not less than 0.1 percent bymass but not more than 50 percent by mass. 7.-13. (canceled)